REVIEW

Dendritic cells and humoral immunity in humans

Hideki Ueno1, Nathalie Schmitt1, A Karolina Palucka1,2,3 and Jacques Banchereau1,2,3

Dendritic cells (DCs) orchestrate the innate and adaptive immune systems to induce tolerance and immunity. DC plasticity and

subsets are prominent determinants in the regulation of immune responses. Our recent studies suggest that humoral and cellular

immunity is regulated by different myeloid DC subsets with distinct intrinsic properties in humans. Although antibody response

is preferentially mediated by CD14+ dermal DCs, cytotoxic T-cell response is preferentially mediated by Langerhans cells (LCs).

Thus, mechanisms whereby DCs induce humoral and cellular immunity seem to be fundamentally distinct. In this review, we will

focus on the role of DCs in the development of humoral immunity. We will also discuss the mechanisms whereby DCs induce

CD4+ T cells associated with aiding B-cell response, including T follicular helper (Tfh) cells, and why human LCs lack this

ability.

Immunology and Cell Biology (2010) 88, 376–380; doi:10.1038/icb.2010.28; published online 23 March 2010

Keywords: human; dendritic cells; langerhans cells; CD4+ T cells; T follicular helper cells

Dendritic cells (DCs) induce/maintain tolerance to self and immunityto nonself by integrating the innate and adaptive immune systems.1,2

Generating the right type of immune response can be a matter of lifeand death. In leprosy, for instance, the tuberculoid form of the diseaseis characterized by a Type I response that keeps the disease in check,whereas the lepromatous form induces an often fatal Type IIresponse.3

Dendritic cells are endowed with enormous functional plasticity,which permits them to induce different immune responses accordingto the microenvironment. In addition, the DC system is composed ofsubsets associated with the induction of different types of immunity.We have recently shown that two myeloid DC (mDC) subsets inhuman skin, that are, Langerhans cells (LCs) and CD14+ dermal DCs,are engaged in the induction of different types of adaptive immunity.4

Although LCs are very efficient at inducing cytotoxic T lymphocyte(CTL) responses, CD14+ dermal DCs display a unique propertyto promote the development of antibody responses (Figure 1).In this review, we will briefly summarize the phenotypical andfunctional differences between human LCs and CD14+ dermal DCs,and discuss how human DCs are involved in the regulation ofhumoral responses.

EPIDERMAL LCs AND CD14+ DERMAL DCs

Human skin hosts at least three different mDC subsets.CD1ahighCD14–HLA-DR+ LCs reside in epidermis, whereasCD1adimCD14–HLA-DR+ DCs (CD1a+ dermal DCs) and CD1a–

CD14+HLA-DR+ DCs (CD14+ dermal DCs) are present in thedermis.4 CD14+ dermal DCs express CD163 and FXIIIa, which arealso expressed by dermal macrophages. However, CD14+ dermal DCsexpress CD11c, whereas dermal macrophages do not.5

The CD14+ dermal DCs express a broad spectrum of surfaceC-type lectins including DC-SIGN, DEC-205, LOX-1, CLEC-6,Dectin-1 and DC immunoreceptor (DCIR).6 In contrast, LCs expressa more limited set, including Langerin and DCIR. Neither of thetwo dermal DC subsets express Langerin, an observation thatcontrasts with the presence of Langerin+ dermal DCs in mice.7–9

CD14+ dermal DCs also express multiple toll-like receptors (TLRs)recognizing bacterial components, such as TLR 1, 2, 4, 5, 6, 8 and106,10, suggesting their involvement in the induction of antibacterialimmunity. LCs have been reported to express TLR1, 2, 3, 6, (7)and 10,10–12 and to respond to ligands of TLR2 (peptidoglycan11and Pam3CysSerLys4 (Pam3CSK4)13) or TLR3 (Poly I:C11,12).In contrast, a study showed that LCs poorly respond to TLR ligandsderived from bacteria, including TLR2, TLR4 and TLR5.10

Our microarray studies using highly purified LCs failed to showmuch TLR expression,6 whereas CD14+ dermal DCs showed signifi-cant expression.

LCs PROMOTE CTL RESPONSES

Human LCs are remarkable at inducing CTL responses in vitro. Forexample, on loading with tumor-derived peptides, LCs effectivelyprime peptide-specific naıve CD8+ T cells and induce their differ-entiation into CTLs that express high levels of cytotoxic molecules andare accordingly efficient at killing tumor cells.4 Notably, induction ofCTL response by LCs does not seem to be dependent on interleukin 12(IL-12) or interferon-a (IFN-a), as neither CD40 nor TLR stimulationinduce LCs to secrete these cytokines.4,11,12,14 Instead, CD40-stimula-tion induces LCs to secrete IL-15,4,14 which we surmise responsible fortheir capacity to induce potent CTL responses. This hypothesis ispartly supported by the observation that externally added IL-15

Received 3 February 2010; accepted 9 February 2010; published online 23 March 2010

1Baylor Institute for Immunology Research and INSERM U899, Dallas, TX, USA; 2Department of Gene and Cell Medicine, Immunology Institute, Mount Sinai School of Medicine;New York, NY, USA and 3Division of Clinical Immunology, Department of Medicine, Immunology Institute, Mount Sinai School of Medicine; New York, NY, USACorrespondence: Dr H Ueno or J Banchereau, Baylor Institute for Immunology Research, 3434 Live Oak, Dallas, TX 75204, USA.E-mails: HidekiU@BaylorHealth.edu or jacquesb@baylorhealth.edu

Immunology and Cell Biology (2010) 88, 376–380& 2010 Australasian Society for Immunology Inc. All rights reserved 0818-9641/10 $32.00

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enhances the ability of CD14+ dermal DCs to develop CTLs with highlevels of cytotoxic granules.6

Langerhans cells also induce a potent proliferation of allogeneicnaıve CD4+ T cells. Naıve CD4+ T cells primed by LCs secretelarger amounts of Type II cytokines than those primed by the twodermal DC subsets.4 A recent report showed that human LCs alsopromote the development of IL-22-secreting CD4+ T cells, which donot coexpress Th1, Th2 or Th17 cytokines.15 Interestingly, IFN-g-secreting CD4+ T cells are induced at a similar level by LCs and otherdermal DC subsets. However, the developmental mechanism ofTh1 cells induced by these DC subsets seems be distinct. Consistentwith their inability to secrete IL-12, induction of Th1 cells byepidermal LCs was shown to be independent of IL-12 or IL-2312.Considering the potent capacity of LCs to induce CTL responses, theTh1 cells primed by LCs might be efficient helpers for the develop-ment of CTL responses.

ROLE OF PLASMACYTOID DCs IN ANTIBODY RESPONSE

In vitro studies with plasmacytoid DCs (pDCs) isolated from humanblood and tonsils show that pDCs are also directly involved in aidingB-cell responses. On stimulation with influenza virus, pDCs promotethe differentiation of memory B cells toward antibody-secretingplasma cells through sequential steps. Type I IFN secreted by pDCspromotes the differentiation of CD40-stimulated B cells into nonanti-body-secreting plasmablast. Similar to mDCs, IL-6 secreted by pDCsfurther induces the transition of nonsecreting plasmablasts into anti-body-secreting plasma cells.16 pDCs activated with TLR9 ligand arealso capable of inducing TLR9-triggered naıve B cells to differentiateinto IgM-producing plasma cells.17

pDCs also contribute to the humoral immunity through crosstalkwith mDCs. Type I IFN secreted by pDCs induces mDCs andmonocytes to express BAFF and APRIL18 that promote B cell

survival, proliferation and class-switching.19 Furthermore, a studycarried out on mice showed that mDCs exposed to Type I IFNin vivo promote the differentiation of naıve CD4+ T cells towardhelper CD4+ T cells that promote antibody responses,20 that is, Tfollicular helper (Tfh) cells.

CD14+ DERMAL DCs DIRECTLY PROMOTE PLASMA CELL

DEVELOPMENT THROUGH IL-12

A decade ago, in vitro studies with CD14+ DCs generated from CD34+

hematopoietic precursor cells have shown that CD14+ DCs induce thedifferentiation of CD40-activated naıve B cells into IgM-producingplasma cells through direct interactions.21 In contrast LCs, bothin vitro generated and ex vivo isolated, lacked this capacity.21,22

Mechanistic studies revealed that IL-12, secreted by CD14+ DCs, iscritical for the first step of plasma cell differentiation. Cooperation ofIL-12 and IL-6 further induces transition from a nonsecreting plas-mablast to IgM-producing plasma cells.23 Indeed, CD14+ DCs, bothin vitro generated and skin derived, secrete multiple proinflammatorycytokines such as IL-1b, IL-6, IL-10, IL-12, tumor necrosis factor-aand granulocyte–macrophage-colony-stimulating factor in response tostimulation through CD40, whereas LCs do not.4,11,12 Thus, the lack ofsecretion of IL-12 and IL-6 seems to explain the inability of LCs tohelp naıve B cells through direct interactions.

CD14+ DERMAL DCs INDUCE DEVELOPMENT OF HELPER

T CELLS

The CD14+ dermal DCs also promote antibody responses indirectlythrough skewed differentiation of naıve CD4+ T cells. Both in vitro-generated CD14+ DCs and skin-derived CD14+ dermal DCs inducenaıve CD4+ T cells to differentiate into effectors capable of helpingB-cell responses. In this case, CD4+ T cells primed by CD14+ dermalDCs are efficient at inducing naıve B cells to become antibody-secreting plasma cells producing IgM, as well as at switching isotypestoward IgG and IgA.4 In contrast, in spite of Th2 cytokine secretion,CD4+ T cells primed by LCs lack the capacity to induce B cells todifferentiate into antibody-secreting cells. These observations indicatethat CD4+ T cells primed by LCs or CD14+ dermal DCs differfunctionally in their ability to help B cells.

CD4+ T CELLS ASSOCIATED WITH B CELL HELP

The requirement of T cell help in the development of antibodyresponses was first described in 1960s.24 CD4+ T cells were found tobe necessary to develop germinal centers, a discrete structure insecondary lymphoid organs in which selection of high-affinityB cells and development of B-cell memory occur.25,26 In vitro studiesin 1980s, mostly using CD4+ T-cell clones and recombinant cytokines,had concluded that Th2 is the major Th subset engaged in the help ofB cells through the secretion of IL-4 and IL-10.27,28 Recent extensivestudies on CD4+ T cells present in germinal centers in mice andhumans have established a novel Th subset, named Tfh cells, repre-senting CD4+ T cells specialized in aiding humoral responses.29–32

Tfh cells express the chemokine (C–X–C motif) receptor 5(CXCR5),29,33,34 which drives their migration into B-cell follicle, asthe ligand, CXCL13, is produced by follicular stromal cells includingfollicular DCs.35,36 Several factors have been identified to be essentialfor Tfh cells to help B cells. These include surface molecules such asCD40 ligand (CD40L)27 and ICOS.37 In particular, Tfh cells secrete thecytokine IL-21,33,38 which drives the growth, differentiation andisotype switching of B cells.39,40 Tfh cells secrete larger amounts ofIL-21 than other conventional Th subsets, including Th1, Th2 andTh17 cells.

CD14+

dermal DCs

LCs

Follicle

CD4

CD4

B

LNs

CD8

ASCTfh

Th2 CTLTh1 Th22

Figure 1 CD14+ dermal DCs preferentially induce humoral immunity,

whereas Langerhans cells induce cellular immunity. On activation, epidermalLCs and CD14+ dermal DCs migrate to the secondary lymphoid organs

through afferent lymphatics. Dermal DCs migrate into the outer paracortex,

just beneath the B-cell follicles, whereas LCs migrate into the T-cell-rich

area. LCs are efficient at inducing high-avidity cytotoxic CD8+ T cell and

Th1, Th2 and Th22 cell responses. In contrast, CD14+ dermal DCs are

efficient at inducing the differentiation of naıve B cells into antibody-

secreting cells (ASC) and at promoting the development of T follicular helper

(Tfh) cells. CD4+ T cells primed by LCs might be efficient at helping the

development of CTL responses.

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Immunology and Cell Biology

HUMAN DCs INDUCE IL-21-PRODUCING HELPER CD4+

T CELLS THROUGH IL-12

In mice, IL-21 itself is critically involved in the generation of Tfhcells.41,42 IL-21 provides a positive feedback loop to CD4+ T cells, andinduces human43 and mouse41,42,44–47 naıve CD4+ T cells to secretemore IL-21. However, as naıve CD4+ T cells or DCs do not secreteIL-21, IL-21-producing CD4+ T cells need to be induced throughinteraction with DCs. In mouse, IL-6 derived from DCs seems to bethe major cytokine involved in the induction of CD4+ T cells to secreteIL-21.20,44,48,49 In contrast, in humans, we and others showed thatIL-12 is the major cytokine by which DCs promote the developmentof IL-21-producing CD4+ T cells.50,51 Similar to Tfh cells,52 CD4+ Tcells induced by activated human DCs help B-cell responses throughIL-21.50 IL-12 is the most potent DC-derived cytokine at inducingnaıve human CD4+ T cells to become IL-21+ CD4+ T cells.50

Consistently, activated DCs induce IL-21-producing helper CD4+

T cells through IL-12, as blocking IL-12 during DC–T-cell coculturepotently inhibit their development.50 The induction of IL-21+CD4+

T cells by DCs might represent the first key step in the development ofhuman Tfh cells. Alternatively, the induced IL-21-producing helperCD4+ T cells might be also associated with plasma cell differentiationat extrafollicular sites.

Notably, human naıve CD4+ T cells, stimulated with activated DCs,differentiate into two different types of IL-21+CD4+ T cells: IFN-g+

IL-21+ Th1 cells expressing T-bet and IFN-g�IL-21+ non-Th1 cells.Both IL-21+CD4+ T cells are dependent on signal transducer andactivator of transcription 4 (STAT4) for their development by IL-12.IL-21 and IL-23 also contribute to the development of IL-21+CD4+

T cells, but at a much lesser extent. IL-21 and IL-23 induce thedevelopment of IFN-g�IL-21+ non-Th1 cells in a STAT3-dependentmanner50 (Figure 2). Thus, in humans, both STAT4 and STAT3pathways contribute to the development of IL-21+CD4+ T cells.DCs regulate the balance of IFN-g+IL-21+ Th1 cells and IFN-g�IL-21+ non-Th1 cells through multiple pathways. For example, naıveCD4+ T cells primed in the presence of IL-12 and IL-23 promote thedevelopment of IFN-g�IL-21+ non-Th1 cells (Schmitt et al. Unpub-lished observation). It is still under investigation as to which type ofIL-21+CD4+T cells, IFN-g+IL-21+ Th1 cells or IFN-g�IL-21+ non-Th1cells display more potent capacity to help B cells.

DISTINCT IMMUNOMODULATORY CAPACITY OF IL-12

BETWEEN MICE AND HUMANS

Of note, the IL-12–IL-21 axis for T helper cell development does notseem to operate in the mouse immune system, as IL-12 does notinduce mouse naıve CD4+ T cells to secrete IL-21. Conversely, IL-6, apotent inducer of IL-21 in mouse CD4+ T cells, does not induce IL-21expression in human naıve CD4+ T cells.50 Thus, DC subsets and theiractivation paths involved in the development of IL-21+CD4+ T cellsmight differ between mice and humans. Accordingly, the in vivobiological effect of IL-12 might also differ between mice and humans.Studies carried out on mice have shown that IL-12, when administeredas vaccine adjuvant, enhances the development of tumor-specific CTLand Th1 responses in vivo.53,54 In humans, the systemic administrationof IL-12 has thus far shown only very modest clinical efficacy.55,56 Theinjection of IL-12 into tumor sites of head and neck cancer patientsresulted in the activation of B cells in the draining lymph nodes.57

Thus, IL-12 and the adjuvants that promote secretion of IL-12might improve vaccines aimed at induction of neutralizing antibodiesin humans.

Taken together, IL-12, a cytokine traditionally viewed as a potentinducer of Type I response, also contributes to humoral responsesin humans. It acts through two independent paths: a direct path inDC–B-cell interaction and an indirect path through DC–T-cell inter-action by developing IL-21+ helper CD4+ T cells (Figure 3). These twopaths might act simultaneously in vivo through the ‘menage a trois’formation of antigen-presenting DCs with antigen-specific T cells andB cells at extrafollicular sites, as recently illustrated through in vivoimaging in mice.58,59

ROLE OF DCs IN THE DEVELOPMENT OF TFH CELLS

Tfh cells express the transcription factor, B-cell lymphoma 6 (Bcl-6),60

which is essential for the development of germinal center B cells.61,62

Recent studies carried out on mice have indicated that Bcl-6 isnecessary and sufficient for the development of Tfh cells in vivo.63–65

On the contrary, Blimp-1, a transcription factor repressing thefunction of Bcl-6, inhibits the generation of Tfh cells.65 Furthermore,downregulation of Blimp-1 in CD4+ T cells promotes their differ-entiation into Tfh cells. Thus, development of Tfh cells is reciprocallyregulated through two transcription factors, Bcl-6 and Blimp-1.

IL-12

IL-23

STAT4

STAT4STAT3

IL-21+IFN-γ +

Th1

IL-21+IFN-γ -

Non-Th1

mDC

NaïveCD4

Figure 2 Human activated DCs induce IL-21-producing T follicular helper

(Tfh)-like cells through IL-12. IL-12 induces human naıve CD4+ T cells to

differentiate into two different types of IL-21-producing CD4+ T cells: IFN-

g+IL-21+ Th1 cells expressing T-bet and IFN-g�IL-21+ non-Th1 cells. BothIL-21-producing CD4+ T cells develop in a STAT4-dependent manner. IL-23

induces only IFN-g�IL-21+ non-Th1 cells through STAT3. The induction of

IFN-g�IL-21+ non-Th1 cells by IL-12 seems to be partially dependent on

STAT3 as well.

IL-12

IL-21

IL-12

DCsB

CD4+

Plasma cells

Figure 3 Possible involvement of IL-12 secreted from DCs in the

development of antibody responses during DC–T cell–B cell ‘menage a trois’

complex. When DCs form complex with T cells and B cells at extrafollicularsites, IL-12 derived from activated DCs promotes B cells to differentiate into

antibody-secreting cells (ASCs) by two different paths: a direct path through

DC–B interaction and an indirect path through induction of IL-21-producing

helper cells.

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Immunology and Cell Biology

However, Bcl-6 does not regulate IL-21 secretion in mouse CD4+

T cells,64,65 in contrast to other transcription factors engaged in thedifferentiation of other Th subsets, namely, Th1, Th2 and Th17 cells,regulating the secretion of cytokines typical of each subset. HowBcl-6 expression leads to the generation of Tfh cells remains to beestablished.

Another key question is when and how naıve CD4+ T cells primedby DCs regulate the expression of Bcl-6 and Blimp-1, and commit tothe Tfh developmental pathway. Differentiation of naıve CD4+ T cellstoward other conventional Th subsets is mainly regulated by thesignals that they receive from DCs during cognate interactions. If thegeneration of Tfh cells shares the same mechanism, which signals fromDCs favor the upregulation of Bcl-6 in naıve CD4+ T cells rather thantranscription factors associated with other Th subsets? Cytokinesinducing IL-21 in CD4+ T cells, that is, IL-6 in mice64 and IL-12 inhumans,51,66 have been shown to upregulate Bcl-6 mRNA expressionin activated naıve CD4+ T cells. However, as the induction of Bcl-6mRNA by these cytokines seems to be transient, other factors derivedfrom DCs might be involved in the regulation of Bcl-6 expression. It isalso possible that acquisition of IL-21-producing ability and expres-sion of Bcl-6 are regulated through independent processes, but notconsequent events.

Alternatively, CD4+ T cells primed by DCs might regulate theexpression of Bcl-6 and Blimp-1 after they encounter B cells. Studiescarried out on mice showed that interaction of primed CD4+ T cellsand B cells is essential for the development of Tfh cells in vivo.65,67

Furthermore, mouse CD4+ T cells deficient in the expression of SAPdo not differentiate into Tfh cells in vivo owing to the lack of stableinteraction with B cells.68 This mechanism might also operate inhumans, as SAP deficiency results in human X-linked lymphoproli-ferative disease, in which the germinal center formation and humoralimmunity is profoundly impaired.69,70 Thus, the major role of DCs inthe development of Tfh cells might be the induction of Tfh precursorscapable of forming long-lasting interaction with antigen-presentingB cells. In this case, the location of migratory sites of DCs in secondarylymphoid organs will be critical. Notably, studies carried out on miceshowed that dermal DCs on activation migrate into the outerparacortex just beneath the B-cell follicles, whereas LCs migrate intothe T-cell-rich inner paracortex71 (Figure 1). This observation furthersupports the fact that dermal DCs, rather than LCs, are the major DCsubset associated with the development of humoral immunity.

FUTURE DIRECTIONS

Considerable progresses in the knowledge of human DC biologyclearly open the avenues for development of novel strategies in clinicalinterventions. The capacity of LCs and CD14+ dermal DCs topreferentially prime cellular immunity and humoral immunity,respectively, has significant implications, most particularly in thecontext of novel human vaccines. Targeting LCs will be importantfor the design of vaccines that aim at eliciting strong CTL responses,whereas targeting CD14+ dermal DCs will be optimal to induce strongantibody responses.

Understanding the role of DCs in the regulation of humoralimmunity is an underdeveloped research area. Further phenotypicaland functional characterization of Tfh cells and their precursors willprovide a fertile ground to understand how DCs regulate antibodyresponses through their development. Of note, Tfh cells seem to becomposed of subsets secreting different sets of cytokines72–76 thatdifferentially regulate isotype switching of B cells. Subsets within Tfhcells are also present in humans (Morita et al. Unpublished observa-tions). Accordingly, DCs stimulated through different paths might

induce different Tfh subsets. Establishing the mechanisms whereby theDC system induces Tfh cells with different functions will facilitate thedesign of novel vaccines. In particular, establishing how DC systemgenerates Tfh subsets associated with the induction of mucosal-homing plasma cells will provide a significant insight in the develop-ment of novel mucosal vaccines.

ACKNOWLEDGEMENTSWe thank former and current members of the Institute for their contributions

to our progresses. These studies have been supported by the NIH (P01

CA084514, U19 AI057234, U19 AI082715, R01 CA089440 and CA078846), the

Dana Foundation, the Baylor Health Care System Foundation, the ANRS and

the INSERM. KP holds the Michael A. Ramsay Chair for Cancer Immunology

Research. JB holds the Caruth Chair for Transplant Immunology Research.

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